Certain 6-isothiocyanobenzothiazoles

ABSTRACT

1. AN ISOTHIOCYANOBENZOTHIAZOLE COMPOUND OF THE FORMULA   2-((R5,R6,R7-PHENYL)-Y-),5-(S=C=N-)-BENZOTHIAZOLE   WHEREIN ONE OF R5,R6 AND R7 IS HYDROGEN, FLUORINE, CHLORINE, BROMINE, ALKYL OF FROM ONE TO FOUR CARBON ATOMS, METHOXY, PHENYL OR ISOTHIOCYANO; EACH OF THE OTHERS OF R5,R6 AND R7 IS HYDROGEN, CHLORINE OR METHYL; AND Y IS OXYGEN OR SULFUR.

United States Patent 3,840,550 CERTAIN 6-ISOTHIOCYANOBENZOTHIAZOLES PaulBrenneisen, Basel, Thomas Wenger, Riehen, Basel- Stadt, Jean-JacquesGallay, Magden, Aargau, and Wolfgang Schmid, Neuallschwil, Switzerland,assignors to Ciba-Geigy Corporation, Ardsley, N.Y.

No Drawing. Filed May 22, 1972, Ser. No. 255,334 Claims priority,application Switzerland, May 24, 1971, 7,542/71 Int. Cl. C07d 91/44 US.Cl. 260-304 15 Claims ABSTRACT OF THE DISCLOSURE Newisothiocyanobenzazoles, process for the production and compositionscontaining these isothiocyanobenzazoles having anthelminthic activity inwarm blooded animals.

The present invention relates to new isothiocyanobenzazoles, toprocesses for their production, as well as to anthelmintic agentscontaining these new isothiocyanobenzazoles as active substance.

Among the endoparasites to be found in warm-blooded animals, thehelminthes, in particular, are ones causing a great deal of harm. Thus,for example, the infestation of animals by worms leads not only to aretardation in growth, but also to the frequent occurrence of damage sosevere that it can result in the death of the affected animals. It istherefore of the greatest importance that agents be developed which aresuitable for the control of helminthes and of their development stages,as well as for the prevention of infestation by these parasites. Anumber of substances having anthelmintic action have become known; butfrequently these are not able, however, to fully satisfy therequirements: either they have an inadequate effect in compatible doseswith undesirable sideetfects, however, in the case of therapeuticallyeffective doses, or they possess too narrow a range of action. Forexample, d,l-2,3,5,6-tetrahydro-6-phenyl-imidazo-[2,1 thiazole, knownfrom the Dutch Pat. No. 6,505,806, is effective only against nematodes,but not against trematodes and cestodes. In addition,isothiocyanobenzazole derivatives having anthelminthic activity areknown from the Belgian Pat. No. 599,413.

In the present description the term helminthes applies to nematodes,cestodes and trematodes; in particular, therefore, to worms of thegastrointestinal tract, of the liver and of other organs.

The new anthelmintically effective isothiocyanobenzazoles correspond tothe general formula I:

N R5 R R A l R I X R4 X represents oxygen, sulphur, or the group NRwherein R represents hydrogen, alkyl, alkenyl, alkanolyl, alkylsubstituted by benzoyl or halogenated benzoyl, benzene 3,840,550Patented Oct. 8, 1974 optionally substituted by halogen, or phenyl orbenzyl optionally substituted by alkyl,

Y represents oxygen, sulphur, or the group NR wherein R representshydrogen, alkyl or alkenyl,

Z represents a straight-chain or branched alkylene bridge member, and

n represents the number 0 or 1,

with the proviso that, among the radicals R to R the isothiocyano groupsare, in each case, only in the mor p-position to hydroxy or alkylaminogroups, and that, if Y represents the NH- group and n equals 0, thesubstituents R and R do not represent isothiocyano, as well as theiraddition salts and quaternary salts non-toxic in anthelminticallyeffective doses for the organism of warmblooded animals.

Y is preferably oxygen, sulphur, the group NH or NCH The aliphaticbridge-member Z is preferably ethylene or vinylene.

The above-mentioned substituents R and R of the groups NR and NR,respectively, represents in preferred compounds of the general formulaI: hydrogen or alkyl.

The alkyl radicals mentioned in the above definition of the substituentsof the general formula I preferably contain 1 to 4 carbon atoms; thecorrespondingly defined alkenyl radicals preferably 3 or 4 carbon atoms.

Suitable non-toxic salts of compounds of the general formula I arepreferably the acid addition salts non-toxic in anthelminticallyelfective doses for the organism of warm-blooded animals.

By addition salts are preferably meant the salts of the followinginorganic and organic acids: hydrohalic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulphuric acid, fiuoboric acid (HBFperchloric acid, alkylsulphuric acid such as methylor ethyl-sulphuricacid, naphthoic acids, benzoic acid, halogenobenzoic acids, acetic acid,halogenoacetic acids such as trichloroacetic acid, aminoacetic acid,propionic acid, halogenopropionic acids, butyric acid, lactic acid,stearic acid, aliphatic dicarboxylic acids such as oxalic acid, tartaricacid, maleic acid, aromatic sulphonic acids such as p-toluenesulphonicacid, etc. Such inorganic and organic acids are likewise suitable forthe formation of quaternary salts of the pyrimidine derivatives offormula I wherein R and/or R represent a trialkylammonioalkyl radical.

The new isothiocyanobenzazoles of formula I are produced according tothe invention by the reaction of an aminobenzazole of formula H:

R1 R2 /N Q R3 i X R4 (II) wherein each one of the substituents R to Rand/or each one of the substituents R to R represent(s) the amino group,and the remaining substituents of the benzene nucleus A eachindependently represent hydrogen, halogen, nitro, hydroxy, alkyl,alkoxy, halogenalkyl, and those of the benzene nucleus B eachindependently represent hydrogen, halogen, nitro, cyano, alkyl, alkoxy,halogenalkyl, alkylamino, dialkylamino, alkanoylamino, or phenyl, or twosubstituents in the ortho-position with respect to each other representa benzene nucleus bound to the nucleus B, and the symbols X, Y, Z and nhave the meanings given under formula I, with the proviso that, amongthe radicals R to R the amino groups are,

in each case, only in the -mor p-position with respect to hydroxyoralkylamino groups, and that, if Y denotes the NH group and n equals 0,the substituents R and R do not represent amino, the said reaction beingperformed with a reagent capable of converting the amino groups intoisothiocyanato groups, preferably in the presence of a solvent ordiluent inert to the reactants.

Suitable reagents capable of introducing a thiocarbonyl group in theprocess according to the invention are given below:

(a) A thiocarbonic acid derivative of the general formula II:

Ha1-CS-Y (II) wherein Hal represents chlorine or bromine, and Yrepresents chlorine, bromine, or a dialkylamino group,

and by which definition is preferably meant thiophosgene, which isoptionally reacted in the presence of an acidbinding agent attemperatures of between 0 and 75, and N,N-diethylthiocarbamoyl chloride,which is reacted at temperatures of between 40 and 200;

(b) A bis-thiocarbamoylsulphide of the general formula III:

fi Alkyl CN Alkyl Alkyl g Alkyl (III) wherein the index m represents thenumber 1 or 2, and alkyl preferably denotes ethyl, in the presence ofhydrogen halide;

(c) Pentathio-dipercarbonic acid-bis-trichloromethyl ester;

((1) Ammonium rhodanide in the presence of gaseous HCl;

(e) Phosgene and phosphorus pentasulphide;

(f) Carbon disulphide in the presence of an inorganic or organic base;the amino group is firstly converted into the dithiocarbamic acid salt,which is then dehydrosulphated to the isothiocyano group;

(g) Ammonium rhodanide and benzoyl chloride, and thermal decompositionof the intermediate thiourea to the isothiocyano derivative;

(h) Carbon disulphide and dicyclohexylcarbodiimide in the presence of atertiary amine;

(i) The new isothiocyanobenzazoles of formula I can also be obtained bya process in which, instead of amine, a corresponding nitro, nitroso,azo or azoxy compound is reacted under pressure (1) with carbondisulphide, carbon oxysulphide, or mixtures of carbon disulphide andcarbon oxysulphide, in the presence of potassium hydrogen sulphide, withtetraalkylurea as the solvent (cp. German Ofienlegungsschrift No.1,954,483);

(2) with carbon oxysulphide in the presence of potassium fluoride and asolvent (aliphatic, aromatic, cycloaliphatic hydrocarbon), likewiseunder pressure (cp. German Oifenlegungsschrift No, 1,954,484).

The reaction with thiophosgene is performed, for example, according toHouben-Weyl, 4th edition, vol. 9, p. 867 onward (1955); and withemployment of acidbinding agents according to O. E. Schultz in Arch,Pharm., 295, 146-151 (1962); the reaction with N,N-diethylthiocarbamoylchloride is carried out according to Org. Chem., 30, 2465 (1965); thatwith bis-thiocarbamoylsulphides according to F. H. Marquardt, Helv.Chim. Acta, 49, 1716 (1966), that with pentathiodipercarbonicacidbis-trichloromethyl ester according to R. Gottfried, Angew. Chem.(Applied Chem), 78, 985 (1966), that with ammonium rhodanide and HCl gasaccording to the 4 British Pat. No. 1,099,768, and the reaction withphosgene and phosphorus pentasulphide according to Houben- Weyl, 4thedition, vol. 9, p. 867 onward. The dehydrosulphation following thereaction with carbon disulphide and bases can be performed oxidativelywith metal salts (British Pat. No. 793,802, Dutch Pat. No. 81,326); itcan be performed, e.g. with lead-, copper-, zincor iron-III-salts,iodine, alkali metal hypochlorites or -chlorites, preferably with sodiumand potassium salts (French Pat. No. 1,311,- 855), also with suitableacid halides such as with phosgene and phosphorus oxychloride [D. Martinet al., Chem. Ber. 98, 2425-2426 (1965)], as well as with C1 andammonium sulphide (German Auslegeschrift No. 1,192,- 189), orchloroamine T (British Pat. No. 1,024,913).

The reaction with ammonium rhodanide and benzoyl chloride, which firstlyleads to the thiourea derivative which is converted by heating, e.g. inboiling chlorobenzene, into the isothiocyano derivative, is performed,for example, according to Houben-Weyl, 4th edition, vol. 9, page 867onward; and the reaction with carbon disulphide anddicyclohexylcarbodiimide, in the presence of a tertiary amine, iscarried out according to J. C. Jochims, Chem. Ber., 10], 1746 (1968).

Examples of inert solvents or diluents which can be used in the processaccording to the invention are as follows:

aliphatic and aromatic hydrocarbons,

aliphatic and aromatic halogenated hydrocarbons,

ethers and ethereal compounds, ketones, amides such asdimethylformamide, etc., water, or mixtures of such solvents with water.

The benzazole compounds embraced by formula II wherein X stands for thegroup NH can be converted by reaction with conventional acylating,alkylating or alkenylating agents into the corresponding derivatives.

The amines serving as starting materials may be used in the form of thefree bases, and also as addition salts with acids, particularly withmineral acids.

The aminobenzazoles embraced by formula II and serving as startingmaterials are, in some cases, described in the literature; or they canbe produced by known processes, e.g. by catalytic hydrogenation, or bythe Bchamp reduction of the corresponding nitro compounds which can beobtained, amongst other means, by nitration of suitable benzazoles (cp.Houben-Weyl-Miiller, Methods of Organic Chemistry, vol. XI/ 1, 1957).

The production of such nitrobenzazoles is generally known.Nitrosubstituted 2-anilino'benzimidazoles can be obtained, for example,by the reaction of phenylor p-chlorophenylcarbonimidoyl-dichloride witho-phenylenediamines substituted by nitro groups (cp. J. Org. Chem., 29,1613-1615, 1964). 5,4'-dinitro-l-anilinobenzothiazole can be producedfrom s-di-p-nitrophenylthiocarbamide with ring formation by the actionof bromine, and a subsequent reducing treatment (see J. Chem. Soc.,1929, 464). Suitable benzazoles, which are substituted on the aromaticnuclei with sulphonamide groups, can also be subjected to hydrolysis,whereby the corresponding aminobenzazoles are obtained. Furthermore,various processes have already been described for the production of theaminobenzazoles to be used as starting materials in the processaccording to the invention in which processes the starting compounds areZ-halogen-benzazoles; these are reacted with suitably substitutedphenols, thiophenols or anilines to give the corresponding2-phenoxybenzazoles (cp. French Pat. No. 1,242,962, Chemical Abstracts,55, 2192821), phenylthiobenzazoles (cp. J. Chem. Soc. (B) 1968, 1280'-1284), or anilinobenzazoles (Ann. Chimica, 44, 3-10, 1954; Helv. Chim.Acta 44, 1273-1282, 1961). Compounds of the type1-aminoalkyl-2-anilinobenzimidazoles can be produced by the ring-closurereaction of 2-(alkylaminoalkylamino) anilines with S-methylisothioureas(cp. U.S,A. Pat. 3,000,898).

According to a type of reaction not hitherto described, substitutedbenzimidazoles corresponding to formula II can be obtained which,according to the invention, can be used as starting materials for thepresent invention. For this purpose, a suitably substituted2-halogenbenzimidazole of the formula:

alkyl, and Hal denotes halogen, preferably chlorine, is reacted with anaminophenol of the formula:

wherein the radicals R to R each independently represent hydrogen,halogen, nitro, cyano, alkyl, alkoxy, halogenalkyl, amino, alkylamino,dialkylamino, alkanoylamino, phenyl, or two substituents in theortho-position With respect to each other represent a bound benzenenucleus, and the amino group is preferably in the mor p-position withrespect to the hydroxy group. The reaction is performed in the presenceof a strong base (KOH, NaOH), preferably in an equimolar amount Withrespect to the benzimidazole. On the other hand, the aminophenol ispresent in excess, preferably in an excess of 2 moles per mole ofbenzimidazole. The reaction is performed at 140-145 C., with separationby distillation of the formed water. The product essentially obtainedwith o-aminophenol is 2-( 1'-hydroxyanilino)-henzimidazoles.

On account of their excellent anthelmintic activity, the newisothiocyanobenzazoles of the following formula III:

wherein the radicals R R R R and R as well as the symbols Y, Z and n,have the meanings given under formula I, with account being taken of thedefined exceptions, whereby the isothiocyano group in the nucleus A isin the 5- or 6-position, and/or that in the nucleus B in the 2(o)-,3(m)- or 4(p)-position with respect to the bridge member, are ofparticular importance.

The benzazole compounds according to the invention and their saltsdisplay a pronounced anthelmintic action against the most importantnematodes infesting animals and human beings (e.g. ascaridae,trichostronglidae, ancylostomatidae, strongylidae), cestodes (e.g.anoplocephalidae, taeniidae) and trematodes (e.g. fasciolidae,schistosomidae). The control of helminthes is of special significance inthe case of domestic animals and productive livestock, such as, e.g.cattle, pigs, horses, sheep,

goats, dogs, cats, as well as poultry. The active substances accordingto the invention can be administered to the mentioned animals either assingle doses or as repeated doses. A better effect is obtained in somecases by a protracted administration of the active substances, or it ispossible, in other cases, to obtain the desired effect with smalleroverall doses. The active substances, or mixtures containing them, mayalso be added to the feed or to the water, the active substanceconcentrations then being between 0.01 and 1%.

The new active substances can be administered to the animals direct,orally or abomasally, in the form of solutions, emulsions, suspensions(drenches), powders, tablets, boluses and capsules, the administrationbeing either in the form of a single dose or in the form of repeateddoses. In some cases, a better effect is achieved by a protractedadministration, or a lesser amount as an overall dose may sufiice. Theactive substances, or mixtures containing them, can also be added to thefeed or to the water, or they may be contained in so-called feedpremixtures.

The usual carriers are used for the preparation of the dosage units,such as kaolin, talcum, bentonite, sodium chloride, calcium phosphate,carbohydrates, cellulose powders, cottonseed meal, Carbowaxes, gelatine,or liquids such as water, optionally with the addition of surface-activesubstances such as ionic or non-ionic dispersing agents, as Well as oilsand other solvents harmless to the organism of animals. If theanthelmintic agents are in the form of feed concentrates, then suitablecarriers are, e.g. productive feeds, fodder grain or proteinconcentrates. Such feed concentrates may contain, in addition to theactive substances, additives, vitamins, antibiotics, chemotherapeutics,bacteriostatics, fungistatics, coccidiostatics, hormone preparations,substances with an anabolic action, or other substances promotinggrowth, or improving the quality of the meat of slaughter cattle, oruseful in some other way for the organism of animals.

Suitable dosage units for oral administration, such as drages ortablets, preferably contain 100 to 500 mg. of the active substanceaccording to the invention, that is, 20 to of a compound of the generalformula I. The dosage units are produced by the combining of the activesubstance with, for example, solid pulverulent carriers such as lactose,saccharose, sorbitol, mannitol, starches such as potato starch, maizestarch or amylopectin, also laminaria powder or citrus pulp powder,cellu lose derivatives or gelatin, optionally with the addition oflubricants such as magnesium or calcium stearate, or polyethyleneglycols, to form tablets or drage cores. The last-mentioned are coatedwith, e.g. concentrated sugar solutions which can also contain, e.g. gumarabic, talcum and/ or titanium dioxide; or with a lacquer dissolved inreadily volatile organic solvents or solvent mixtures. It is alsopossible to add dyestuffs to these coatings, e.g. for the identificationof the various doses of active substance.

In the following are described certain tests carried out to determinethe anthelmintic activity of the new benzazoles of the general formulaI.

Determination of the anthelmintic activity on fowl infested withAscaridia galli Oneto three-day old chickens were artificially infestedwith eggs of Ascaridia galli (ascarids). Groups each of 5 chickns wereused for each test. The active substances were administered to thechickens 4 to 5 weeks after infestation, the administration being in theform of a single dose per day on three successive days. Infestedchickens which had not been treated with the active sub stances weretaken as a control.

Evaluation.The number of Ascaridia gaIli discharged by each test groupin the course of 5 days after the first administration of the activesubstance was determined daily, and also the number found on examinationon the 5th test day in the intestines. Furthermore, the number ofchickens free from worms was determined.

N0. ofAscaridz'a galli from 5 chicks Discharged during duration of testDaily In dose, percent Ing./kg. Absoof Found No. of of body lute totalon diswormtree General Active substance weight N0. N 0. section chickenscondition 2-phenoxy-6-isothiocyano-l,3-benzothiaz0le 750 108 100 Good.2-(3-chlorphenoxy)-6-isothiocyano-1,8-benzothiazole 750 219 100 0 5 Do.2(2-chlorphenoxy)-6-isothiocyano-1,3-benzothiazole- 750 61 100 0 5 Do.2-(4-finorophenoxy) -6isothiocyano-1,3-benzothiazole 750 113 100 0 5 D0.2- (4-meth ylphenoxy)-6-isothiocyano-1,S-benzothiazole- 7 50 60 100 0 5Do. 2-(3 -methoxy-phenoxy)-6-isothioeyano-1,3-benz0thiazo1e 750 116 1000 5 Do. 2-(2-fluorophenoxy)-6-isothiocyano-1,3-benzothiazo1e 750 80 100O 5 Do. 1-n1ethyl-2-(p-isothiocyanophenylthio)-benzimidazole-chlorhydrate 750 182 100 0 5 D0.2-(3-isothiocyanophenoxy)-l-methylbenzimidazole-hydrochloride 750 231 968 3 Do.

Tests on mice infested by Hymenolepsis nana The active substances wereadministered in the form of a suspension by means of a stomach probe towhite mice artificially infested with Hymenolepsis nana. Five animalswere used per test. The active substances were administered once dailyto each group of animals on three suc cessive days. The animals werekilled and dissected on the 8th day after commencement of the treatment.

After dissection of the test animals, an evaluation was D aily dose, mg./kg. Infestation of body of the five Infestation of the control animalsActive substance weight test mice on dissection2-(n-isothioeyano-phenylamino)-b enzoxazole 750 0-0-0-0-0/ 4/ L1-13/L/1-15/ L-18/L/ l-20/ L/ 1 2-phenoxy-6-isothiocyano-1,3-benzothiazolc750 0-0-0-0-0 6/L/1-8/L/1-9/L/1-1l/L/l-13/L/124-isothi0cyano-phenylthio)-1,3-benzothiazole 750 0-0-0-0-6/L/1-8/L/1-9/L/1-11/L/1-l3/L/12-(3-bromophenoxy)-6-isothiocyano-1,3-benzothiazole- 566 0-0-0-0-010/L/l13/L/1 2-(4-fiuorophenoxy)-6-isothiocyano-1,3-benzothiazole. 7500-0-0-0-0/ 2/L/1-4/L/1-4/L/1-19/L/1-1l/L/l 2-(2'-methylphenoxy)-6-isothiocyano-1,3-benzothiazole 750 0-0-0-0-0 8/51/1177 L/l-14/L/1-16/ L/ 1- 0 12'(4-methylphenoxy)-6-is0thiocyan0-l,S-benzothiamle 750 0-0-0-0-04/15-8/L/1-8/L/1-8/L/12-(2-i'iuorophenoxy)-6-isothiocyano-1,3-benzoth.iazole 750 00-000/0/L1-3/L-1524 2-(4-1sothiocyanophenoxy)-1,3-benzqthiazole 750 00O-0/02-5/L/1-5/L/1-10/L/1-13/L/1 2-(4' -isothiocyanatophenoxy)-5-isoth1ocyanobenzoimidazole 750 0-0-0-0-2 4/L/1-5/L/1-5/L/1-6-6/L/l2-(2-methy13-methoxy-phenoxy)-6-isothiocyano- 1,3-benzothiazole 7500-0-0-0-0 5/ L/ 1-6-6/1-7-15/ L/ l 2- (3-isothiocyanophenoxy) -1-methyl-benzoimidazolehydrochloride 750 0-0-0-0-1 0/ L-1-3/ L1524 made by acount of the tapeworms present 1n the mtes- Tests on rats infested byFasczola hepatica tines. Untreated mice which had been infested at the 5same time and in the same manner served as a control.

The agents were well tolerated by the miceand no resulting symptoms wereobserved.

White laboratory rats are artifically infested with Fasciola hepatz'ca.At the end of the prepatent time, the infestation of the rats byFasciola hepatica (common liver Daily dose, Infestation mgJkg. of the 5test Infestation of the of body mice on controlmiceon Active substancesweight dissection dissection 2-(m-isothiocyano-phenylamlno) -benzoxazole750 0-0-0-00 2711-1924 2-phenoxy-fi-isothiocyano-1,3-benzothiazole 7500-0-0-0-0 10-12-14-17-222-(4-isothiocyano-phenoxy)-6-isothiocyano-1,3-benzothiazole. 750 0-0-12-15-16-19-25 2-(3'-chlor0phenoxy)-6-isothiocyano-1,3-benzothiazole 750O O-O-O-Z 12-15-16-19-25 2- (4-fluorophcnoxy) -6-isothiocyano-1,3-benzothiazole 750 0-0-0-0-1 2-4-5-8-20 2- (2 ,3 ,5-trimethyl-phenoxy) -5-isothiocyano-1,3-benzothiazole 7 0-00-00 0-1-2-2-42-(2-methylphenoxy)-6-isothiocyano-1,3-benzothiazo1e 750 000-O-13-4-15-18-19 2(4-methylphenoxy)-6-isothiocyano-1,3-benzothiazole 7500-0-0-0-0 7-8-12-16-20 2-(2 ,4 ,5 -trimeth ylphenoxy) -6-isothioeyano-1,3-b enzothiazole- 750 0-0-0-0-2 4-5-6-6-112-(2-fluorophenoxy)-6-isothiocyano-1,3-benzothiazole 750 0-0-0002-6-7-11-16 2-( y-isothiocyano-phenoxy)-1 3-benzothiazole 750 0-0-0-0-010-16-17-26-33 2-[-isothiocyano-phenylamino-5-isothiocyanobenzimidazole.2-[4'-isothiocyano-phenylthio]-benzimidazole2-(3-isothiocyanopbenoxy)-benzimidazo1e2-(4-isothioeyanophenoxyg-benzimidazole 2-(2'-isothiocyanophenoxy-1-methyl-benzimidazole-hydrochlor1 e 2-(3-isothiocyanophenoxy)-1-methy1-benzimidazole2-(g-isothiocyanophenoxy)l-methyl-benzimidazole-hydroch1o- Tests on miceinfested by oxyuris fluke) was determined by means of 3 successiveanalyses of the excrement.

In each test, 4 infested rats are treated with the active substance,administered in the form of a suspension by stomach probe, once daily onthree successive days. In the 3rd to 5th week after administration ofthe active substance, an excrement analysis is carried out once week- 1yto determine the content of eggs of the common liver fluke (Fasciolahepatica). The test animals are killed at the end of the th week aftercommencement of the test, and an examination made of the number ofcommon liver fluke still present.

obtain 29.3 g. of(3'-isothiocyanophenoxy)-l-methylbenzimidazole-hydrochloride, M.P. 154to 158 C.

6 parts of this product are treated with a saturated sodium bicarbonatesolution. The obtained base is taken up in chloroform. After drying anddistillation of the Excrement (3) examination No. of Daily egg dischargecommon dose in liver mg./kg Before After fluke of body medimediafterGeneral Active substance weight cation cation dissection condition2-phenoxy-fi-isothiocyano-l,3-benzothiazo1e 200 P0si Nega- 0-0-0-0 Good2-(4'-fluorophenoxy)-6isothioeyano-l,3-benzothiazole- 200 tive. tive.(Hi-(H3 Do. 2-(2-methy1phenoxy)-6-isothiocyano-l,3-benzothiazole 200 dodo 0-0-0-0 Do. 2-(2-fluorophenoxy)-6-isothiocyano-l,3-benzothiazole 200do .d0 0-0-0-0 Do. 2-[4-isothiocyano-phenylthio]-benzimidazole 150 do.do 0-0-0-0 Do. 1-methy1-2-(p-isothioeyanophenylthio)-benzimidazole- 200do "do..." 0-0-0-0 Do.

chlorhydrate. 2-(3lliisotahiocyanophenoxy)-benzimidazole-hydro- 200 do..do 0-1-0-0 Do.

0 on e. 2-(3-isothioeyanophenoxy)-1-methyl-benzimidazole- 200 do ..do0-0-0-0 D0.

hydrochloride. 2-(3-isothiocyanophenoxy)-l-methyl-benzimidazole 200 dodo. 00-00 Do. 2-(4-isothiocyanophenoxy)-1-methyl-benzimidazole 200 do do0-0-0-0 Do. 2-(4-isothiocyanophenoxy)-1-methyl-benzimidazole- 200 ..do.do 0-0-0-0 Do.

hydrochloride. 2(i gothiocyanophenoxw-benz1rmdazole sulphuric 150 do do0-0-0-0 Do.

aci sat.

The following examples serve to further illustrate the productionprocesses according to the invention. Where not otherwise stated, theterm parts denotes parts by weight; the temperatures are expressed indegreescentigrade.

Example 1.6-isothiocyano-2-phenoxybenzothiazole An amount of 8.46 g. ofthiophosgene in a sulphonating flask is stirred into 500 ml. of icewater. An addition is then made dropwise, in the course of 10 minutes,of a solution of 18 g. of 6-amino-2-phenoxybenzothiazole in 100 ml. ofdioxane as well as 10 ml. of water. The suspension is further stirredovernight at room temperature. The formed precipitate is separated andwashed with water; the residue is dissolved in 100 ml. of methylenechloride, and the solution dried over sodium sulphate. Afterchromatography with methylene chloride through aluminium oxide (neutral,activity stage III), an amount of 12.5 g. of6-isothiocyano-2-phenoxybenzothiazole, M.P. 118 to 119 C., is obtained.

Example 2.2- (3 -isothiocyanophenoxy) -1- methylbenzimidazole (a) Anamount of 74.6 g. of 3-aminophenol is heated, under nitrogen, with 24 g.of 80% ground potassium hydroxide to 100; an addition is then made atthis temperature of 57 g. of 2-chloro-1-methylbenzimidazole. The mixtureis subsequently heated to 140 to 145 and maintained for 5 hours at thistemperature, whilst the Water forming is continuously distilled off. Themixture is then diluted whilst still hot with 100 ml. ofdimethylformamide, and poured on to 1500 ml. of water. The formedprecipitate is filtered 01f under suction and, While still moist, boiledwith 400 ml. of ethanol with the addition of active charcoal. Afterfiltration, the filtrate is diluted with 400 ml. of water and the wholestirred. 2-(3-aminophenoxy)- l-methylbenzimidazole, M.P. 110 to 114,precipitates out.

(b) An amount of g. of thiophosgene, 250 ml. of dioxane and 100 ml. ofwater is placed into a sulphating flask and cooled to 0 to 5; anaddition is then made dropwise Within 30 minutes, of a solution of 61 g.of 2(3- aminophenoxy)-l-methylbenzimidazole in 200 ml. of dioxane. Themixture is stirred for 3 hours at 0 to 5 it is afterwards furtherstirred for 15 hours at room temperature. After dilution with 600 ml. ofwater, the precipitate is separated and stirred, for 7 hours at 10, intoa solution of 10 g. of thiophosgene in 500 ml. of acetone. The productis separated and recrystallised from acetonitrile to solution, theresidue, recrystallised from cyclohexane, yields 4.2 g. of2-(3'-isothiocyanophenoxy)-l-methylbenzimidazole, M.P.: 121124 C.

Example 3.-(Compoundsee Example 2) An amount of 4.8 g. of 2-(4'-aminophenoxy)-1-methylbenzimidazole is stirred with 2.3 g. ofbis-(trichloromethane-sulphonyl-trithiocarbonate in 25 ml. of Water for24 hours at room temperature. The precipitate is separated, washed withsodium bicarbonate solution, and taken up in chloroform. After dryingand distillation of the chloroform solution, the residue is boiled outwith cyclohexane, filtered hot, and the filtrate diluted with petroleumether. The 2-(4'-isothiocyanophenoxy)-1 methylbenzimidazolecrystallising out melts at 59 to 61 C.

Example 5 .-2- 4'-isothiocyanophenoxy l ,3-dimethylbenzimidazolium-iodide An amount of 14.3 g. of2-(4'-isothiocyanophenoxy)- l-methylbenzimidazole is refluxed with 6.8g. of methyl iodide in 50 ml. of anhydrous acetone for 21 hours. Thesolution is then diluted with ether, the precipitate filtered off, andthe filtrate concentrated by evaporation to dryness to obtain 16 g. of2-(4'isothiocyanophenoxy)-l,3-dimethylbenzimidazolium iodide, M.P.: 204to 208 C.

Example 6 (a) A solution of 83 g. of p-nitroaniline in 400 ml. ofdioxane is added at room temperature, with stirring, to 126 g. of2-chloro-6-nitrobenzoxazole obtained from 43.3 g. of 2-chlorobenzoxazolewith fuming nitric acid (d. 1.52) in sulphuric acid. The solution isheated to 40 C. and stirred at this temperature for a further 19 hours.The solution is diluted with 200 ml. of water; it is then cooled and theprecipitate separated. The suction-filter residue is dried and dissolvedin 500 ml. of dimethylformamide. This solution is purified, and dilutedwith 200 ml.

1 l of ethanol. The precipitating 6-nitro-2-(4-nitroanilino)-benzoxazole has the melting point 305 to 310 C.

(b) LAH amount of 47 g. of 6-nitro-2-(4'-nitroanilino)- benzoxazole isdissolved in 500 ml. of dimethylformamide; and 7 g. of palladiumcharcoal (5%) then added. Within 3 hours at room temperature, 18.6 ml.of hydrogen is absorbed. The catalyst is then filtered off, and thefiltrate concentrated in a water-jet vacuum at 70 C. to dryness. Theresidue is afterwards dissolved with 250 ml. of 2-n HCl, and thesolution rendered alkaline with concentrated ammonia solution.6-amino-2-(4'-aminoanilin)-benzoxazole, M.P. 83 to 87, precipitates.

(c) A suspension of 17.2 g. of 6-amino-2-(4'-amino anilino)-benzoxazolein 200 m1. of anhydrous chlorobenzene is saturated at room temperaturewith hydrogen chloride. An amount of 13.2 g. of NH SCN (ammoniumthiocyanate) is subsequently added to the mixture. With a further slightintroduction of hydrogen chloride, the reaction mixture is refluxed,with stirring, for 6 hours. After cooling, the crystallisate isseparated and recrystallised from methyl ethyl ketone. The obtained6-isothiocyano-2-(4' isothiocyanophenylamino)-benzoxazole has themelting point 233 to 237 C.

Example 7.2-(4'-fluorophenoxy)-6- isothiocyanobenzothiazole An amount of20 g. of phosgene is introduced, with ice cooling and with the exclusionof atmospheric moisture, into 100 ml. of o-dichlorobenzene; an additionis then made at 0 of 13 parts of2-(4'-fluorophenoxy)-6-aminobenzothiazole. The reaction mixture isstirred overnight at room temperature; the temperature is then raised,with a slight introduction of phosgene, within 45 minutes to 90. Theflow of phosgene is thereupon stopped, and stirring at 125 -130continued until the evolution of gas has finished (after ca. 2 hours).After slow cooling to room temperature, 3.75 g. of phosphoruspentasulphide is added; stirring with refluxing is subsequently carriedout for 14 hours, and the solution filtered off whilst still hot. Thefiltrate is concentrated by evaporation, and the residue chromatographedthrough aluminium oxide with methylene chloride as the eluant. Theobtained 2-(4'-fluorophenoxy)-6-isothiocyanobenzothiazole has the M.P.124-126.

Example 8 .2- 2'-fluorophenoxy) -6- isothiocyanobenzothiazole An amountof 17 g. of ammonium rhodanide is dissolved in 200 ml. of absoluteacetone; an addition is then made to the solution, with stirring, of 31g. of benzoyl chloride. The reaction mixture is allowed to boil withrefluxing for minutes; a solution is then added of 57 g. of2-(2'fluorophenoxy)-6-aminobenzothiazole (obtained from2-(2'-fluorophenoxy)-6-nitrobenzothiazole by catalytic hydrogenation,cp. Example 6) in 400 m1. of acetone. Stirring is continued for 2minutes at the boiling temperature, and the mixture then poured, withstirring, into 5000 ml. of ice water. Filtration is performed, thefilter residue washed with water, and suspended in 350 ml. of 10% sodiumhydroxide solution. The suspension is quickly brought to boilingtemperature and allowed to boil for a further 2 minutes. Cooling is thenrapidly carried out in an ice bath; the suspension is neutralised with2-n hydrochloric acid, and the pH-value adjusted with 2-n ammonia to 8.Filtration is again performed, the filter residue washed with wateruntil neutral, and dried at 80 in vacuo. The finely powdered material issuspended in 500 ml. of anhydrous chlorobenzene and refluxed for 14hours. After the solvent has been evaporated ofl', the residue ischromatographed through aluminium oxide with methylene chloride as theeluant. The obtained 2-(2'-fluorophenoxy) 6 isothiocyanobenzothiazolemelts at 115-117.

1 2 Example 9.2- (4'-isothiocyanophenylthio benzothiazole Hydrogenchloride is introduced for minutes, with cooling, into a mixture of 12.9g. of 2-(4-aminophenylthio)-benzothiazole (obtained from2-(4'-nitrophenylthio)-benzothiazole by catalytic hydrogenation, seeExample 6) and 15.4 g. of bis-(diethyl)-thiocarbamoyl-disulphide in 250ml. of anhydrous chlorobenzene. Stirring is afterwards carried out for 4/2 hours with refluxing, animal charcoal is added and filtrationperformed hot. The filtrate is concentrated by evaporation, andchromatographed through aluminium oxide with methylene chloride as theeluant. 2-(4'-isothiocyanophenylthio)-benzothiazole is obtained, whichmelts at 84.5 86.

Example 10.--2- (4-methylphenoxy) -6- isothiocyanobenzothiazoleAdditions are made dropwise, at -10 to 5, firstly of 31 ml. oftriethylamine and then of 4.3 ml. of carbon disulphide to 18.4 g. of2-(4-methylphenoxy)-6-aminobenzothiazole in 360 ml. of absolute diethylether. Stirring is continued for ca. 12 hours at room temperature; themixture is cooled to 0, and an addition made at this temperature, within30 minutes, of 6.7 ml. of phosphorus oxychloride in 80 ml. of absolutediethyl ether. After 10 hours stirring at room temperature, filtrationis performed; the filter residue is washed firstly with diethyl etherand then with water and dried. The product is afterwards chromatographedthrough aluminum oxide, with methylene chloride as the eluant, to obtain2-(4- methylphenoxy)-6-isothiocyanobenzothiazole, M.P. 121 123.

The active substances listed in the following table are obtained by theprocedures described in the preceding examples.

Melting point Compounds: 1n C.

2-phenoxy-6-isothiocyano 1,3 benzothiazole 188-119 2-(3'-chlorophenoxy)6 isothiocyano 1,3-benzothiazole 102-103 2-(4-ch1orophenoxy) 6isothiocyano- 1,3-benzothiazole -112 2-(2'-chlorophenoxy) 6isothiocyano- 1,3-benzothiazole 123-125 2-(3,4'-dichlorophenoxy) 6isothiocyano-1,3-benzothiazole 140-142 2-(3'-brornophenoxy) 6isothiocyano- 1,3-benzothiazole 109-111 2-(4'-bromophenoxy) 6isothiocyano- 1,3-benzothiazole 111-113 2-(4-iodophenoxy) 6isothiocyano- 1,3-benzothiazole 105-107 2(2'-bro1nophenoxy) 6isothiocyano- 1,3-benzothiazole 123-125 2-(3-trifluoromethylphenoxy 6isothiocyano-1,3-benzothiazole 80-82 2-(2'-methyl-4-chlorophenoxy) 6isothiocyano-1,3-benzothiazole 101-103 2-(3'-methy1phenoxy) 6isothiocyano- 1,3-benzothiazole 76.5-77.5 2-(2-methylphenoxy) 6isothiocyano- 1,3-b enzothiazole 115-117 2-(2,5-dirnethylphenoxy) 6isothiocyano-1,3-benzothiazole 78-80 2-(2',4-dimethylphenoxy) 6isothiothiocyano-1,3-benzothiazole 116-118 2-(3',5'-dimethylphenoxy) 6isothiocyano-1,3-benzothiazole 100-101 2-(2,3,5-trimethylphenoxy) 6isothiocyano-1,3-benzothiazole 99-100 2-(2',4',5-trimethylphenoxy 6isothiocyano-1,3-benzothiazole 83-85 8. A compound according to Claim 2which is 2-(3- methoxyphenoxy)-6-isothiocyano-1,3-benzothiazole.

9. A compound according to Claim 2 which is 2-(2- fluorophenoxy)-6-isothiocyano-1,3-benzothiazole.

10. A compound according to Claim 2 which is 2-(4- 5isothiocyanophcnoxy)-6-isothiocyano-1,3-benzothiazole.

11. A compound according to Claim 2 which is 2-(2',3,5-trimcthylphcnoxy)-6-isothiocyano 1,3 benzothiazole.

12. A compound according to Claim 2 which is 2-(2- 1O mcthylphenoxy)-6-isothiocyan0-1,3 -benzothiazole.

13. A compound according to Claim 2 which is 2-(2',4,5-trimcthylphcnoxy)-6-isothiocyano 1,3 bcnzothiazole.

14. A compound according to Claim 2 which is 2-(4'- 15isothiocyanophcnylthio)6-isothiocyano 1,3 bcnzothiazole.

15. A compound according to Claim 2 which is 2-(3-bromophenoxy)-6-isothiocyano-1,3-benzothiazole.

References Cited UNITED STATES PATENTS Narayanan ct a1. 260'-309.2

RICHARD J. GALLAGHER, Primary Examiner US. Cl., X.R.

1. AN ISOTHIOCYANOBENZOTHIAZOLE COMPOUND OF THE FORMULA